Sargassum species are tropical and sub-tropical brown macroalgae (seaweed) of shallow marine meadow. These are nutritious and rich source of bioactive compounds such as vitamins, carotenoids, dietary fibers, proteins, and minerals. Also, many biologically active compounds like terpenoids, flavonoids, sterols, sulfated polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, pheophytine were isolated from different Sargassum species. These isolated compounds exhibit diverse biological activities like analgesic, anti-inflammatory, antioxidant, neuroprotective, anti-microbial, anti-tumor, fibrinolytic, immune-modulatory, anti-coagulant, hepatoprotective, anti-viral activity etc., Hence, Sargassum species have great potential to be used in pharmaceutical and neutralceutical areas. This review paper explores the current knowledge of phytochemical, therapeutic potential, and health benefits of different species of genus Sargassum.

As more than 70% of the world's surface is covered by oceans, the wide diversity of marine organisms offer a rich source of natural products, which make up approximately one half of the total global biodiversity and are rich reservoirs of structurally diverse bio-functional components. Among marine organisms, marine algae are rich sources of structurally diverse bioactive compounds with various biological activities. [1],[2]

Marine algae are heterogeneous group of plants with a long fossil history. Two major types of algae can be identified: The macroalgae occupy the littoral zone, and the microalgae are found in both bentheic and littoral habitats and also throughout the ocean waters as phytoplankton. Marine macroalgae or seaweeds are found in the coastal region between high tide to low tide and in the sub-tidal region up to a depth where 0.01% photosynthetic light is available and can be classified into three classes: Brown algae (Phaeophyta), Green algae (Chlorophyta), and Red algae (Rhodophyta). Brown seaweeds are predominantly brown due to the presence of the carotenoid fucoxanthin, and the primary polysaccharides present include alginates, laminarins, fucans, and cellulose. Green seaweeds are dominated by chlorophyll a and b, with ulvan being the major polysaccharide component. While in Red seaweeds, principal pigments are phycoerythrin and phycocyanin and the primary polysaccharides are agars and carrageenans. [3],[4] The importance of seaweeds for human consumption is well known since 300 BC in China and Japan. These two countries are the major seaweed cultivators, producers, and consumers in the world. In the Indian Ocean region countries like Malaysia, Indonesia, Singapore, Thailand, Korea etc., seaweeds are used in salad, jelly, soup etc., However, in India, seaweed consumption is negligible except in the preparation of porridge from Gracilaria species and Acanthophora species in coastal states of Kerala and Tamil Nadu. [5] Seaweeds are rich in soluble dietary fibers, proteins, minerals, vitamins, antioxidants, phytochemicals, and polyunsaturated fatty acids, with low caloric value. [6] They are an excellent source of vitamins A, B l , B 2 , B 3 , B 12 , C, D, E. Their amino acid content is well-balanced and contains all or most of the essential amino acids needed for life and health. [5] Moreover, biologically active compounds isolated from marine macroalgae exhibit various biological activities such as antioxidant, [7],[8] anti-viral, [9] anti-allergic, [10] anti-inflammatory, [11],[12] anti-cancer, [13] anti-coagulant [14]etc.

Sargassum, a genus of brown seaweed, commonly known as gulf-weed or sea holly belonging to family Sargassaceae, order Fucales, subclass Cyclosporeae, and class Phaeophyceae, contains approximately 400 species. [15],[16]Sargassum species are found throughout tropical and subtropical areas of the world and are reported to produce metabolites of structural classes such as terpenoids, polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, plastoquinones, steroids, glycerides etc., which possesses several therapeutic activities. As it possesses many pharmacological properties, it has been considered as a medicinal food of the twenty-first century, and research is being carried out on it to reveal its other pharmacological properties. This review focuses on pharmacological activities with potential health benefits of different Sargassum species.

Therapeutic potential of sargassum species

In vitro antioxidant activity

Oxidative stress is the result of an imbalance between pro-oxidant and antioxidant homeostasis that leads to the generation of toxic reactive oxygen species (ROS). [17] ROS such as hydroxyl, super oxide, and peroxyl radicals are formed in human tissue cells, which attack macromolecules such as membrane lipids, proteins, and DNA, lead to many health disorders such as cancer, diabetes mellitus, age-related degenerative conditions, neurodegenerative and inflammatory diseases with severe tissue injuries. [18],[19],[20] Antioxidants may have a positive effect on human health as they can protect human body against damage by ROS. In vivo, cells have their own inherited antioxidative defense system, in the form of various enzymatic, as well as non-enzymatic pathways, for removing the ROS. Among enzymatic pathways, O 2 are dismutated by superoxide dismutase (SOD) to H 2 O 2 , catalase (CAT) reduces H 2 O 2 to water and molecular oxygen. Glutathione peroxidase (GPX) catalyzes the reduction of H 2 O 2 to water and organic peroxide to alcohols at the expense of reduced glutathione (GSH), while glutathione-S-transferase conjugates xenobiotics with glutathione for excretion. Among the non-enzymatic substances, β-carotene, vitamin-A, vitamin-E, and vitamin C scavenge free radicals. [21] Among the sources of natural antioxidants, marine seaweeds are now being considered to be a rich source of antioxidants. Antioxidant activities of Sargassum species have been determined by various methods such as 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical scavenging, 2,2'- azinobis-3-ethylbenzo thizoline-6-sulfonate (ABTS) radical scavenging, NO scavenging, lipid peroxide inhibition, superoxide and hydroxyl radical scavenging assays.

Dementia is a chronic progressive mental disorder, which adversely affects memory, thinking, comprehension, calculation, and language. Some of the commonest types of dementia are Alzheimer's disease, Parkinsonism More Details, and Myasthenia gravis. [31] Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease, which resulting in memory loss, behavior disturbances, personality changes, and a decline in cognitive abilities. [32] Substantial reduction in activity of the enzyme choline acetyltransferase (ChAT) responsible for the synthesis of acetylcholine (ACh) is the key marker enzyme in AD. Parkinson's disease, a neurodegenerative disease of the substantia nigra (an area in the basal ganglia), which involves a breakdown of nerve cells in the motor area of the brain, is also characterized by reduction in ChAT activity. [33] Myasthenia gravis, a chronic autoimmune disorder, is characterized by reductions in levels of ACh at the neuromuscular junction. [34] All these disorders are related to abnormalities in the central cholinergic system, which shows a decline in ACh level. The inhibition of acetylcholinesterase (AChE) enzyme, which catalyzes the breakdown of ACh, may be one of the most realistic approaches to the symptomatic treatment of these disorders. [35]

The neurotrophic factor, nerve growth factor (NGF), is fundamentally important to the differentiation, survival, and maintenance by stimulating neurite outgrowth in neuronal and rat phaeochromocytoma (PC12) cells. [39],[40] Reduction of NGF levels in the brain ultimately causing aging and neurodegenerative conditions such as Alzheimer's disease. [41] The use of NGF-potentiating substance with small molecular weight has been suggested for the treatment of neurodegenerative diseases. [42] Furthermore, numerous animal tests have also shown that the administration of NGF can significantly ameliorate the neuronal degeneration in rat cerebral cortex and hippocampus after ischemic insults. [43] These results underlie the rationale for the use of NGF to treat neurodegenerative diseases.

Neurite outgrowth is a fundamental neuronal feature and plays an important role in neuronal development during embryogenesis and in the adult brain. [44] Pheophytin A, purified from the Japanese brown alga Sargassum fulvellum, is a novel neuro-differentiation compound. Pheophytin A at 3.9 μg/mL was observed to synergize with NGF in promoting neurite outgrowth in rat pheochromocytoma PC12 cells by a mechanism that appeared to involve activation of mitogen-activated protein kinase signaling. [45] Sargachromenol isolated from Sargassum macrocarpum was shown to markedly promote NGF-dependent neurogenesis in PC12D cells (ED 50 9 μM). Interestingly, mechanistic studies demonstrated that both the cyclic AMP-mediated protein kinase and mitogen-activated protein kinase 1/2 signal transduction pathways were required for neurite growth stimulated by sargachromenol. [46] Low molecular weight quinonic compound sargaquinoic acid isolated from Sargassum macrocarpum possesses a novel nerve growth factor-dependent neurite outgrowth promoting activity at the nanogram range. Kamei and Tsang investigated the signaling pathways involved using a pharmacological approach and concluded that sargaquinoic acid enhanced neurite outgrowth in PC-12 neuronal cells by involving both TrkA-mitogen-activated protein kinase and adenylate cyclase-protein kinase as a signal transduction pathways. [47] In a subsequent study, the neuroprotective effect of sargaquinoic acid was shown to be independent of nerve growth factor and phosphatidylinositol 3 kinase, a key signaling molecule. [48]

Anti-cancer and cytotoxic activity

Cancer is a leading cause of death worldwide and a diverse group of diseases characterized by the uncontrolled proliferation of anaplastic cells, which tend to invade surrounding tissues and metastasize to other tissues and organs. Cancer results from a mutation in the chromosomal DNA of a normal cell, which can be triggered by both external factors (tobacco, alcohol, chemicals, infectious agents, and radiation) and internal factors (hormones, immune conditions, inherited mutations, and mutations occurring in metabolism). [49]

Zandi et al.[50] reported that the cold water extract of Sargassum oligocystum showed the reasonable anti-cancer activity against tumor cells replication. The most potent activity has been shown at concentrations 500 μg/ml and 400 μg/ml of extract on Daudi and K562 cell lines, respectively. Polysaccharides from Sargassumfusiforme showed significant anti-tumor activity both in vitro and in vivo, and improved the immune function in tumor-bearing mice. [51] Also, two polysaccharide fractions, SP-3-1 and SP-3-2 from Sargassumpallidum, showed significant in vitro anti-tumor activity against the HepG2 cells, A549 cells, and MGC-803 cells. [52] Khanavi et al.[53] found that the hexane fraction of methanol extract of Sargassum swartzii had in vitro cytotoxicity against Caco-2 and T47D cells and increased the percentage of apoptotic cells among these cells. The activity of this fraction may be due to the meroterpenoids. Hydroxysargaquinone and Sargasals I and II fraction of a methanolic extract of Sargassum turtile has demonstrated significant and marginal cytotoxicity against cultured P-388 lymphocytic leukemia cells. [54] Furthermore, polysaccharide E3 isolated from Sargassumlatifolium showed a selective cytotoxicity against lymphoblastic leukemia 1301 cells. [55]

Anti-pyretic, analgesic, and anti-inflammatory activities

The inflammatory process involves a series of events that can be elicited by numerous internal or external stimuli. Therapy of inflammatory diseases is usually directed at the inflammatory processes. Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. [56]

Dar et al.[57] reported that butanolic extract of Sargassum wightii collected during winter season was most effective (86.7%) in reducing carrageenan-induced edema in rats at a dose of 100 mg/kg as compared to reference drugs aspirin (79.4%) and ibuprofen (57.3%). The dichloromethane extract of Sargassum fulvellum inhibited an inflammatory symptom of mouse ear edema by 79.1%. The ethanol extract of Sargassum thunbergii also inhibited edema by 72.1%, when evaluated against yeast-induced pyrexia, tail-flick test, and phorbol myristate acetate-induced inflammation (edema, erythema, and blood flow) in mice. [11] Also, methanolic extracts of Sargassum swartzii at the dose of 500 mg/kg body weight showed analgesic effects in both acetic acid-induced writhing and hot plate-induced pain models, acute anti-inflammatory effect in both edemas in hind paw induced by carrageenan and peritonitis models. Furthermore, S. swartzii extract showed chronic anti-inflammatory effects at the dose of 175 and 350 mg/kg body weight in amiant-induced granuloma model in mice. [58] According to Hwang et al.,[59] fucoidan (sulfated polysaccharide) from Sargassum hemiphyllum showed in vivo and in vitro anti-inflammatory activity.

Hepatoprotective activity

Raghavendran et al.[60] reported the protective effects of Sargassum polycystum alcoholic extract on changes in liver mitochondrial enzymes against acetaminophen-induced toxic hepatitis in rats. Reports show that the S. Polycystum pre-treated rats showed an improved level of mitochondrial GSH, and prevented the excessive depletion of SOD and CAT with concomitant reduction in the levels of lipid peroxides when compared with acetaminophen-induced animals. Furthermore, extract prevent the severe impairment in the activities of tricarboxylic acid cycle enzymes, prevention in the excessive impairment of NADH dehydrogenase activity and improving the mitochondrial antioxidant defence system, thereby protecting the critical nucleophilic sites on the enzymes against toxic electrophilic metabolites. Sulfated polysaccharides from Sargassum wightii significantly restored the deformities due to cyclosporine A-induced oxidative liver injury in rats. Administration of sulfated polysaccharides repairs the activities of hepatic marker enzymes as it decreases the levels of lipid peroxidation, 8-hydroxy-2-deoxy guanosine and protein carbonyls, along with an increase in ATPase activities. Also, sulfated polysaccharides co-administration minimized the oxidants production by scavenging the free radicals. [61]

Disorders in blood coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis). [67] Anti-coagulants are substances that prevent coagulation that is, they stop blood from clotting. [68] De Zoysa et al.[69] reported the isolation and characterization of fucose containing sulfated polysaccharide as an anti-coagulant agent from Sargassum fulvellum. Hot water extracts from Sargassum horneri showed high activated partial thromboplastin time (APTT) and exhibited the potent anticoagulant activity. [70]

Immunomodulatory activity

Immunomodulation is explained as any change in the immune response and may involve induction, expression, amplification of any part or phase in the immune response. Modulation may be very specific limited to a given antigen/agent with a great effect on immune response. [71]In vitro and In vivo effect of ethyl acetate fraction Sargassum ilicifolium was tested for immunomodulatory activities. In vitro study revealed that S. ilicifolium has stimulated chemotatic, phagocytic, and intracellular killing of human neutrophils at a dose of 100 μg/ml. Whereas, In vivo studies have shown prominent immunostimulatory effect at a dose of 100 mg/kg p.o. The said activity was due to presence of terpenes and steroids. [72] The hot-water extract of Sargassum hemiphyllum showed the activity of cell proliferation (174%) at 120 μg/ml, and IgM secretion (132%) at 120 μg/ml when assayed in HB4C5 cells (human hybridomas producing monoclonal antibody against human lung cancer). Furthermore, extract showed significant proliferation activity (141%) and phagocytosis activity (148%) at 80 μg/ml when assayed in J774 (murine macrophage-like) cell line. These result revealed the significant immune-stimulating activity of Sargassum hemiphyllum.[23]

Other biological activities

Other pharmacological activity includes fibrinolytic, anti-diabetic, anti-bacterial, anti-plasmodial, Skin-whitening, gastric-protective activity etc., Two bioactive products identified as 1-O-palmitoyl-2-O-oleoyl-3-O-(α-D-glucopyranosyl)-lycerol (POGG) and 1-O-myristoyl-2-O-oleoyl-3-O-(α-D-glucopyranosyl)-glycerol (MOGG) obtained from Sargassum fulvellum showed fibrinolytic activity in the reaction system of pro-u-PA and plasminogen. [73] According to Kim et al.,[74] Sargaquinoic acid and sargahydroquinoic acid from Sargassum yezoense able to increase Peroxisome proliferator-activated receptor α/γ (PPARα/γ) transcriptional activity. PPARs are members of the nuclear hormone receptor superfamily of ligand- activated transcription factors, and are currently appreciated as potential therapeutic targets for the treatment of diabetes and dyslipidemia. Hot water extract of Sargassum polycystum in dose of 100 mg/kg maintains the acidity of gastric juice and improves the gastric mucosal injury in rats. [75] Extracts of Sargassum polycystum and Sargassum silquastrum exerted in vitro inhibitory activity against tyrosinase and melanin production, which could be developed to a skin-whitening agent in cosmetics industry. [76],[77]

Conclusion

A large number of studies are reported that Sargassum species contain sulfated polysaccharide, plastoquinone, phlorotannins, flucoxanthin, fucoidan, sargaquinoic acid, sargachromenol, steroids, terpenoids, and flavonoids etc., Furthermore, these bioactive compounds and various extracts showed significant therapeutic potential and could be introduced for the preparation of novel functional ingredients in pharmaceuticals for the treatment and or prevention of several disorders. Therefore, further research studies are needed to exploit its maximum therapeutic potential in the field of medicinal and pharmaceutical sciences for novel and fruitful application.

Acknowledgment

Authors are thankful to Dr. A. M. Ittadwar, Principal, Gurunanak College of Pharmacy, Nagpur for his core guidance and necessary support.